Replication-defective adenovirus vectors (rAd) are powerful inducers of cellular immune responses and have therefore come to serve as useful vectors for gene-based vaccines particularly for lentiviruses and filoviruses, as well as other nonviral pathogens (Shiver, et al., (2002) Nature 415(6869): 331-5; Hill, et al., Hum Vaccine 6(1): 78-83; Sullivan, et al., (2000) Nature 408(6812): 605-9; Sullivan et al., (2003) Nature 424(6949): 681-4; Sullivan, et al., (2006) PLoS Med 3(6): e177; Radosevic, et al., (2007); Santra, et al., (2009) Vaccine 27(42): 5837-45.) Adenovirus-based vaccines have several advantages as human vaccines since they can be produced to high titers under GMP conditions and have proven to be safe and immunogenic in humans (Asmuth, et al., J Infect Dis 201(1): 132-41; Kibuuka, et al., J Infect Dis 201(4): 600-7; Koup, et al., PLoS One 5(2): e9015; Catanzaro, et al., (2006) J Infect Dis 194(12): 1638-49; Harro, et al., (2009) Clin Vaccine Immunol 16(9): 1285-92.) While most of the initial vaccine work was conducted using rAd5 due to its significant potency in eliciting broad antibody and CD8+ T cell responses, pre-existing immunity to rAd5 in humans may limit efficacy (Catanzaro, (2006); Cheng, et al., (2007) PLoS Pathog 3(2): e25; McCoy, et al., (2007) J Virol 81(12): 6594-604; Buchbinder, et al., (2008) Lancet 372(9653): 1881-93). This property might restrict the use of rAd5 in clinical applications for many vaccines that are currently in development including Ebolavirus (EBOV) and Marburg virus (MARV).
To circumvent the issue of pre-existing immunity to rAd5, several alternative vectors are currently under investigation. These include adenoviral vectors derived from rare human serotypes and vectors derived from other animals, such as chimpanzees (Vogels, et al., (2003) J Virol 77(15): 8263-71; Abbink, et al., (2007) J Virol 81: 4654-63; Santra, (2009)). Research on the use of animal-derived adenoviral vectors is relatively nascent, while human adenoviruses possess the advantages of having well-characterized biology and tropism on human cells, as well as documented manufacturability (Vogels, et al., (2007) J Gen Virol 88(Pt 11): 2915-24.). Immunogenicity of these vectors and their potential as vaccines has been demonstrated in animal models, primarily as prime-boost combinations with heterologous vectors (Abbink, et al., 2007; Shott et al., (2008) Vaccine 26:2818-23).
Adenovirus seroprevalence frequencies are cohort-dependent (Mast, et al., (2010) Vaccine 28(4): 950-7) but among a large group of 51 human adenoviruses tested, Ad35 and Ad11 were the most rarely neutralized by sera from 6 geographic locations (Vogels, et al., 2003). rAd35 vaccines have been shown to be immunogenic in mice, nonhuman primates, and humans, and are able to circumvent Ad5 immunity (Barouch, et al., (2004) J Immunol 172(10): 6290-7; Nanda, et al., (2005) J Virol 79(22): 14161-8; Ophorst, et al., (2006) Infect Immun 74(1): 313-20; Thorner, et al., (2006) J Virol 80(24): 12009-16; Rodriguez, et al., (2009) Vaccine 27(44): 6226-33). rAd35 vectors grow to high titers on cell lines suitable for production of clinical-grade vaccines (Havenga, et al., (2006) J Gen Virol 87(Pt 8): 2135-43), and have been formulated for injection as well as stable inhalable powder (Jin, et al., Vaccine 28(27): 4369-75). These vectors show efficient transduction of human dendritic cells (de Gruijl, et al., (2006) J Immunol 177(4): 2208-15; Lore, et al., (2007) J Immunol 179(3): 1721-9), and thus have the capability to mediate high level antigen delivery and presentation. Ad26, from subgroup D, is another adenovirus selected for its ability to circumvent Ad5 pre-existing immunity. Although Ad26 seroprevalence can be significant in certain in adult population, Ad26 neutralizing antibody titers remain markedly lower than Ad5 neutralizing antibody titers (Abbink, et al., 2007; Mast, et al., 2010). Studies have shown that rAd26 can be grown to high titers in Ad5 E1-complementing cell lines suitable for manufacturing these vectors at a large scale and at clinical grade (Abbink, et al., 2007), and this vector has been shown to induce humoral and cell-mediated immune responses in prime-boost vaccine strategies (Abbink, et al., 2007; Liu, et al., (2009) Nature 457(7225): 87-91).